title: Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease.
abstract: BACKGROUND
  The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS.
  
  
  RESULTS
  In motor neurons of homozygous symptomatic WR mice, a massive number of endosomal vesicles significantly enlarged (up to 3 μm in diameter) were subjected to ultrastructural analysis and immunohistochemistry for the endosome-specific small GTPase protein Rab7 and for amyloid precursor protein (APP). Enlarged vesicles were neither detected in heterozygous WR nor in transgenic SOD1(G93A) mice; in WR motor neurons, numerous APP/Rab7-positive vesicles were observed which were mostly LC3-negative, suggesting they are not autophagosomes.
  
  
  CONCLUSIONS
  We conclude that endosomal APP/Rab7 staining reflects impaired vesicle trafficking in WR mouse motor neurons. Based on these findings human ALS tissues were analysed for APP in enlarged vesicles and were detected in spinal cord motor neurons in six out of fourteen sporadic ALS cases. These enlarged vesicles were not detected in any of the familial ALS cases. Thus our study provides the first evidence for wobbler-like aetiologies in human ALS and suggests that the genes encoding proteins involved in vesicle trafficking should be screened for pathogenic mutations.
authors.affiliation: Pharmaceutical Science Research Division, King's College London, 150 Stamford Street, London, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Palmisano
authors.forename: Panagiota
authors.initials: P
authors.lastname: Golfi
authors.forename: Peter
authors.initials: P
authors.lastname: Heimann
authors.forename: Christopher
authors.initials: C
authors.lastname: Shaw
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitt-John
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Bartsch
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology*; D001933:Brain Stem / Q000473:pathology; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology*; D009046:Motor Neurons / Q000473:pathology / Q000648:ultrastructure*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020693:rab2 GTP-Binding Protein / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D016564:Amyloid beta-Protein Precursor; C486749:VPS54 protein, human; D033921:Vesicular Transport Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D020691:rab GTP-Binding Proteins; D020693:rab2 GTP-Binding Protein